The overall objective of this proposal is to test the hypothesis that cerebrovasular function is impaired in patients with mild cognitive impairment (MCI) leading to brain hypoperfusion, brain atrophy, white matter lesions and cognitive impairment. Importantly, we will determine whether endurance exercise training improves cerebrovascular function and brain perfusion, thus ameliorating brain atrophy, white matter lesions and cognitive decline in patients with MCI. To accomplish these objectives, we will complete the following specific aims.
Specific aim 1 a: to determine whether baroreflex function is impaired, leading to enhanced blood pressure instability and thus hemodynamic challenges for brain perfusion in patients with MCI.
Specific aim 1 b: To determine whether cerebral autoregulation and cerebral vasomotor reactivity to CO2 are impaired in patients with MCI and whether cerebrovascular dysfunction is associated with atherosclerosis and arterial stiffness.
Specific aim 2 : To determine whether enhanced blood pressure instability in conjunction with cerebrovascular dysfunction leads to brain atrophy, white matter lesions and cognitive impairment.
Specific aim 3 : To determine whether exercise training improves cerebrovascular function, brain perfusion and ameliorates brain atrophy, white matter lesions and cognitive decline in patients with MCI and whether exercise training upregulates brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). Cerebrovascualr function, brain perfusion, brain tissue volume and white matter lesions will be measured using magnetic resonance imaging (MRI) and transcranial Doppler (TCD). Cognitive function will be assessed using a comprehensive battery of neuropsychological tests focused on the executive and memory function. Multiple linear regression models will be used for statistical data analysis.

Public Health Relevance

Alzheimer's disease (AD) is a devastating brain disorder imposing heavy burdens on the society with aging population. Existing therapies are at best, symptomatic and do not prevent or slow the progression of the disease. Mild cognitive impairment (MCI) is likely to be a transitional state between normal aging and AD, suitable for therapeutic interventions. The outcome of this project will provide in-depth understanding of important pathophysiological mechanisms for the control of brain perfusion in patients with MCI. Most importantly, this project will determine whether exercise training improves cerebrovascular function leading to improvement in brain structure and function in patients with MCI. The new knowledge will have significant impact on prevention or treatment of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033106-04
Application #
8312542
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Ryan, Laurie M
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$865,598
Indirect Cost
$144,334
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Tseng, Benjamin Y; Cullum, C Munro; Zhang, Rong (2014) Older adults with amnestic mild cognitive impairment exhibit exacerbated gait slowing under dual-task challenges. Curr Alzheimer Res 11:494-500
Marmarelis, V Z; Shin, D C; Orme, M E et al. (2014) Model-based physiomarkers of cerebral hemodynamics in patients with mild cognitive impairment. Med Eng Phys 36:628-37
Tarumi, Takashi; Dunsky, David I; Khan, M Ayaz et al. (2014) Dynamic cerebral autoregulation and tissue oxygenation in amnestic mild cognitive impairment. J Alzheimers Dis 41:765-78
Liu, Jie; Zhu, Yong-Sheng; Khan, Muhammad Ayaz et al. (2014) Global brain hypoperfusion and oxygenation in amnestic mild cognitive impairment. Alzheimers Dement 10:162-70
Marmarelis, Vasilis Z; Shin, Dae C; Orme, Melissa et al. (2014) Time-varying modeling of cerebral hemodynamics. IEEE Trans Biomed Eng 61:694-704
Monson, Nancy L; Ireland, Sara J; Ligocki, Ann J et al. (2014) Elevated CNS inflammation in patients with preclinical Alzheimer's disease. J Cereb Blood Flow Metab 34:30-3
Tarumi, Takashi; Ayaz Khan, Muhammad; Liu, Jie et al. (2014) Cerebral hemodynamics in normal aging: central artery stiffness, wave reflection, and pressure pulsatility. J Cereb Blood Flow Metab 34:971-8
Marmarelis, V Z; Shin, D C; Orme, M E et al. (2013) Closed-loop dynamic modeling of cerebral hemodynamics. Ann Biomed Eng 41:1029-48
Marmarelis, V Z; Shin, D C; Orme, M E et al. (2013) Model-based quantification of cerebral hemodynamics as a physiomarker for Alzheimer's disease? Ann Biomed Eng 41:2296-317
Tseng, B Y; Gundapuneedi, T; Khan, M A et al. (2013) White matter integrity in physically fit older adults. Neuroimage 82:510-6

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